Modelling and drug targeting of a myeloid neoplasm with atypical 3q26/MECOM rearrangement using patient-specific iPSCs.

Autor: Nakamura M; Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Chonabayashi K; Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Narita M; Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan., Matsumura Y; Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan., Nishikawa M; Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan., Ochi Y; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Nannya Y; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.; Division of Hematopoietic Disease Control, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Hishizawa M; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.; Department of Hematology, Kyoto-Katsura Hospital, Kyoto, Japan., Inoue D; Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan., Delwel R; Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Ogawa S; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Takaori-Kondo A; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Yoshida Y; Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
Jazyk: angličtina
Zdroj: British journal of haematology [Br J Haematol] 2024 Oct; Vol. 205 (4), pp. 1430-1443. Date of Electronic Publication: 2024 Aug 26.
DOI: 10.1111/bjh.19720
Abstrakt: Structural variations involving enhancer hijacking induce aberrant oncogene expression and cause tumorigenesis. A rare translocation, t(3;8)(q26.2;q24), is associated with MECOM and MYC rearrangement, causing myeloid neoplasms with a dismal prognosis. The most recent World Health Organization classification recognises myeloid neoplasms with MECOM rearrangement as acute myeloid leukaemia (AML) with defining genetic abnormalities. Recently, the increasing use of induced pluripotent stem cell (iPSC) technology has helped elucidate the pathogenic processes of haematological malignancies. However, its utility for investigating enhancer hijacking in myeloid neoplasms remains unclear. In this study, we generated iPSC lines from patients with myelodysplastic syndromes (MDS) harbouring t(3;8)(q26.2;q24) and differentiated them into haematopoietic progenitor cells to model the pathophysiology of MDS with t(3;8)(q26.2;q24). Our iPSC model reproduced the primary patient's MECOM expression changes and histone H3 lysine 27 acetylation (H3K27ac) patterns in the MECOM promoter and MYC blood enhancer cluster (BENC). Furthermore, we revealed the apoptotic effects of the bromodomain and extra-terminal motif (BET) inhibitor on iPSC-derived MDS cells by suppressing activated MECOM. Our study demonstrates the usefulness of iPSC models for uncovering the precise mechanism of enhancer hijacking due to chromosomal structural changes and discovering potential therapeutic drug candidates for cancer treatment.
(© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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